The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers

Summary

We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet.

The controlled-release formulation gave less variable plasma metoprolol concentrations, C_max 138 nmol·l⁻¹ and C_min 74 nmol·l⁻¹, whereas for the conventional formulation the mean C_max of metoprolol was 629 nmol·l⁻¹ and the C_min 20 nmol·l⁻¹.

Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P<0.05).

Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable.

Controlled-release metoprolol with hydrochlorothiazide combines effective β₁-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.